From: Rich Murray [rmforall@att.net]
Sent: Monday, August 05, 2002 5:38 AM
To: fdadockets@oc.fda.gov
Subject: RTM: FDA: (Section E) 18 recent formaldehyde toxicity [Comet
assay] abstracts 6.25.1 rmforall
RTM: FDA: (Section E) 18 recent formaldehyde toxicity [Comet assay]
abstracts 6.25.1 rmforall
http://groups.yahoo.com/group/aspartameNM/message/645
[ See also, re formaldehyde neurotoxicity:
http://groups.yahoo.com/group/aspartameNM/message/628
Rich Murray: Professional House Doctors: Singer: EPA: CPSC:
formaldehyde toxicity 6.10.1 rmforall ]
A millenium surge in formaldehyde toxicity research is
noticable at: www.ncbi.nlm.nih.gov/PubMed . The new,
fast, sensitive convenient Comet assay,
which can reveal genetic damage in a single white blood cell,
is being widely used to study the details of cellular damage
from formaldehyde, one of the most potent, cumulative
toxins, produced by the liver from methanol (wood alcohol),
which in turn happens to be 10% of the sweetener
aspartame, used by 200 million, sadly misled by the
incessant industry refrain: "Aspartame is
the most widely tested food additive in history." As a
medical layman, I can safely mention that DNA-protein
crosslinks means: cellular malfunctions and death,
mutations, cancers, and birth defects. I hope some of
these teams will immediately study the white blood
cells of the many aspartame reactors, people who
report a dismaying, bewildering suite of symptoms
after months and years of 1-4 L/day use of diet
drinks, which translates to 56 - 224 mg methanol. Results
could be quickly and definitively achieved that would be
of immense scientific and public health value.
Can a medical doctor send a sample of his patient's
blood to any of these labs for testing? What would be the
procedure, and cost? Could medical insurance support
innovative diagnostic research of the greatest value, for
the patient and for the public? How much genetic damage
arises from daily use of aspartame?
Woodrow C. Monte, Director, Food Science and Nutrition Laboratory
602-965-6938 Arizona State University, woody.monte@asu.edu,
"Aspartame: Methanol and the Public Health," 1984,
J. Applied Nutrition, 36(1), 42-54 (62 references):
The methanol from 2 L of diet soda, 5.6 12-oz cans, 20 mg/can, is
112 mg, 10% of the aspartame. The EPA limit for water is 7.8 mg
daily for methanol (wood alcohol), a deadly cumulative poison.
Many users drink 1-4 L daily. The reported symptoms are entirely
consistent with chronic methanol toxicity. (Fresh orange juice has
34 mg/L, but, like all juices, has 16 times more ethanol, which
strongly protects against methanol.) http://www.dorway.com/wmonte.txt
Here is research in 1998 by C. Trocho et al, using a very low level of
aspartame ingestion, 10 mg/kg, for rats, which have a much greater
tolerance for aspartame than humans. So, the corresponding level for
humans would be about 1 or 2 mg/kg. (Many headache studies in humans
used doses of about 30 mg/kg daily.) This proves that aspartame causes
binding of methanol's product, formaldehyde, a potent, cumulative
toxin, into tissues. Life Sci June 26 1998; 63(5): 337-49
Full report: http://www.presidiotex.com/barcelona/index.html
Formaldehyde derived from dietary aspartame binds to tissue components
in vivo. Departament de Bioquimica i Biologia Molecular,
Facultat de Biologia, Universitat de Barcelona, Spain.
http://www.bq.ub.es/cindex.html LÝnies de Recerca: Toxicitat de
l'aspartame http://www.bq.ub.es/grupno/grup-no.html
Sra. Carme Trocho, Sra. Rosario Pardo, Dra. Immaculada Rafecas,
Sr. Jordi Virgili, Dr. Xavier Remesar, Dr. Jose Antonio
Fernandez-Lopez,
Dr. MariÓ Alemany Fac. Biologia (male)
Tel.: (93)4021521, FAX: (93)4021559
alemany@porthos.bio.ub.es bioq@sun.bq.ub.es josefer@porthos.bio.ub.es
rafecas@porthos.bio.ub.es remesar@porthos.bio.ub.es
Sra. Carme Trocho Fac. Biologia "Trok-ho"
Tel.: (93)4021544, FAX: (93)4021559
Abstract:
Adult male rats were given an oral dose of 10 mg/kg aspartame,
14C-labeled in the methanol carbon. At timed intervals of up to 6
hours, the radioactivity in plasma and several organs was investigated.
Most of the radioactivity found (>98% in plasma, >75% in liver) was
bound to protein. Label present in liver, plasma and kidney was in the
range of 1-2% of total radioactivity administered per g or mL, changing
little with time. Other organs (brown and white adipose tissues,
muscle, brain, cornea and retina) contained levels of label in the
range of 1/12th to 1/10th of that of liver. In all ,the rats retained,
6 hours after administration, about 5% of the label, half of it in
the liver.
The specific radioactivity of tissue protein, RNA and DNA was quite
uniform. The protein label was concentrated in amino acids, different
from methionine, and largely coincident with the result of protein
exposure to labeled formaldehyde. DNA radioactivity was essentially in
a single different adduct base, different from the normal bases present
in DNA. The nature of the tissue label accumulated was, thus, a direct
consequence of formaldehyde binding to tissue structures.
The administration of labeled aspartame to a group of cirrhotic rats
resulted in comparable label retention by tissue components, which
suggests that liver function (or its defect) has little effect on
formaldehyde formation from aspartame and binding to biological
components. The chronic treatment of a series of rats with 200 mg/kg
of non-labeled aspartame during 10 days results in the accumulation of
even more label when given the radioactive bolus, suggesting that the
amount of formaldehyde adducts coming from aspartame in tissue proteins
and nucleic acids may be cumulative.
It is concluded that aspartame consumption may constitute a hazard
because of its contribution to the formation of formaldehyde adducts.
PMID: 9714421, UI: 98378223
********************************************************
Life Sci 1999;65(13):PL157-60
Comments on the purported generation of formaldehyde and adduct
formation from the sweetener aspartame.
Tephly TR Thomas R. Tephly 319-335-7979 thomas-tephly@uiowa.edu
ttephly@blue.weeg.uiowa.edu Department of Pharmacology
The University of Iowa, Iowa City 52242, USA.
A recent paper by Trocho et al. (1) describes experiments meant to
show that formaldehyde adducts are formed when rats are administered
the sweetener aspartame. These authors assume that the methanol carbon
of aspartame generates formaldehyde which then forms adducts with
protein, DNA, and RNA. Doses employed range widely. In this letter,
studies which have been published previously and which were not cited
by these authors are reviewed in order to put into perspective the
disposition of methanol and formaldehyde in monkeys
and humans, species relevant to the toxicity of methanol
and its toxic metabolite, formic acid.
PMID: 10503962, UI: 99431287
A number of pro-aspartame studies by Tephly and associates, invariably
funded by the aspartame industry (Monsanto, NutraSweet) are criticized
in detail at:
"Scientific Abuse in Aspartame Research"
http://www.holisticmed.com/aspartame/abuse/methanol.html
Aspartame Toxicity Information Center Mark D. Gold
www.HolisticMed.com/aspartame 603-225-2100
mgold@tiac.net 12 East Side Drive #2-18 Concord, NH 03301
Carcinogenesis 1996 Jan;17(1):121-5
DNA--protein crosslinks, a biomarker of exposure to formaldehyde--in
vitro and in vivo studies.
Shaham J, Bomstein Y, Meltzer A, Kaufman Z, Palma E, Ribak J
Occupational Cancer Unit, Occupational Health and Rehabilitation
Institute, Loewenstein Hospital, P.O. Box 3, Ra'anana 43100, Israel.
Judith Shaham, MD, is Instructor, Epidemiology and Preventive
Medicine, Sackler Faculty of Medicine, Tel Aviv University. I could
not find an email address for her, but an Associate Professor at her
department is Beni Habot, MD, schmuelh@netfvision.net.il, whose work
at the Geriatric Medical Center at Schmuel Harofe Hospital includes
"poisoning of elderly", according to his website.
Her coauthors are Yonit Bomstein, Alex Meltzer (or Melzer), and Joseph
Ribak. Yonit Bomstein got his PhD in 1996 at Dept. of Immuniology,
Feinberg Graduate School, Faculty of Biology, Weizmann Institute of
Science, Rehovot, Israel, 972-8-934-2111 , 946-6966 fax, email
rscien@weizmann.weizmann.ac.il , where he is a Research Student.
Formaldehyde (FA) is a widely produced industrial chemical. Sufficient
evidence exists to consider FA as an animal carcinogen. In humans the
evidence is not conclusive. DNA-protein crosslinks (DPC) may be one of
the early lesions in the carcinogenesis process in cells following
exposures to carcinogens. It has been shown in in vitro tests that FA
can form DPC. We examined the amount of DPC formation in human white
blood cells exposed to FA in vitro and in white blood cells taken from
12 workers exposed to FA and eight controls. We found a significant
difference (P = 0.03) in the amount of DPC among exposed (mean +/-
SD 28 +/- 5%, minimum 21%, maximum 38%) than among the unexposed
controls (mean +/- SD 22 +/- 6%, minimum 16%, maximum 32%). Of the 12
exposed workers, four (33%) showed crosslink values above the upper
range of controls. We also found a linear relationship between years of
exposure and the amount of DPC. We conclude that our data indicate a
possible mechanism of FA carcinogenicity in humans and that DPC can be
used as a method for biological monitoring of exposure to FA.
PMID: 8565120, UI: 96152634
Int J Occup Environ Health 1997 Apr;3(2):95-104
DNA-Protein Crosslinks and Sister Chromatid Exchanges as Biomarkers
of Exposure to Formaldehyde.
Shaham J, Bomstein Y, Melzer A, Ribak J
Occupational Cancer Unit, Occupational Health and Rehabilitation
Institute, P.O. Box 3, Raanana 43100, Israel.
[Record supplied by publisher]
Formaldehyde is classified as a probable human carcinogen.
DNA-protein crosslinks (DPCs) and sister chromatid exchanges (SCEs) may
represent early lesions in the carcinogenic process. The authors
examined the DPCs and SCEs in peripheral-blood lymphocytes of 12 and 13
workers exposed to formaldehyde and eight and 20 unexposed workers,
respectively. The amounts of DPCs and SCEs in the exposed and the
unexposed differed significantly after adjustment for smoking. There
was a linear relationship between years of exposure and the amounts of
DPC and SCE. The authors conclude that the data indicate a possible
mechanism of carcinogenicity of formaldehyde, and that formaldehyde is
mutagenic to humans. These results support the use of DPCs as a
biomarker of occupational exposure to formaldehyde and to detect
high-risk populations for secondary prevention. PMID: 9891106
Carcinogenesis 1996 Sep;17(9):2097-101
Comments on 'DNA-protein crosslinks, a biomarker of exposure to
formaldehyde--in vitro and in vivo studies' by Shaham et al.
Casanova M, Heck HD, Janszen D
Publication Types: Letter PMID: 8824543, UI: 96421926
Mutat Res 2000 Sep 20;469(2):279-85
Evaluation of DNA damage in workers occupationally exposed to
pesticides using single-cell gel electrophoresis (SCGE) assay.
Pesticide genotoxicity revealed by comet assay.
Garaj-Vrhovac V, Zeljezic D
Mutagenesis Division, Institute for Medical Research and
Occupational Health, Zagreb, Croatia.
The comet assay, also called the single-cell gel
electrophoresis (SCGE) assay, is a rapid and
sensitive method for the detection of DNA damage
(strand breaks and alkali-labile sites) in
individual cells. The assay is based on the embedding
of cells in agarose, their lysis in alkaline
buffer and finally subjection to an electric current.
In the present study, alkaline SCGE was used
to evaluate the extent of primary DNA damage
and DNA repair in peripheral blood lymphocytes
of workers employed in pesticide production.
After the period of high pesticide exposure,
lymphocytes of the occupationally exposed workers
manifested increased tail length and tail
moment compared to the control group. After the
workers spent 6 months out of the pesticide
exposure zone, both endpoints were still above
that of the control but significantly decreased as
compared to the results of the first analysis.
PMID: 10984689, UI: 20442322
Mutagenesis 2000 Jan;15(1):85-90
Induction and repair of formaldehyde-induced
DNA-protein crosslinks in
repair-deficient human cell lines.
Speit G, Schutz P, Merk O
Universitatsklinikum Ulm, Abteilung Medizinische
Genetik, D-89070 Ulm, Germany.
guenter.speit@medizin.uni-ulm.de
We have previously shown that the alkaline Comet
assay (single cell gel electrophoresis) in a
modified version is a sensitive test for the
detection of formaldehyde-induced DNA-protein
crosslinks (DPC). Our results also indicated that
formaldehyde-induced DPC are related to the
formation of chromosomal effects such as micronuclei
and sister chromatid exchanges. To better
understand the genetic consequences of
formaldehyde-induced DPC we have now investigated
the induction and removal of DPC in relationship to
the formation of micronuclei in normal and
repair-deficient human cell lines. We did not find
significant differences between normal cells, a
xeroderma pigmentosum (XP) cell line and a Fanconi
anaemia (FA) cell line with respect to the
induction and removal of DPC. However, the induction
of micronuclei was enhanced in both
repair-deficient cell lines, particularly in XP
cells, under the same treatment conditions.
Comparative investigations with the DNA-DNA
crosslinker mitomycin C (MMC) revealed a
delayed removal of crosslinks and enhanced induction
of micronuclei in both repair-deficient cell
lines. FA cells were found to be particularly
hypersensitive to micronucleus induction by MMC. In
contrast to the results with formaldehyde, induction
of micronuclei by MMC occurred at much
lower concentrations than the effects in the Comet
assay. Our results suggest that more than one
repair pathway can be involved in the repair of
crosslinks and that disturbed excision repair has
more severe consequences with regard to the
formation of chromosomal aberrations after
formaldehyde treatment than has disturbed crosslink
repair. PMID: 10640535, UI: 20109169
Teratog Carcinog Mutagen 2000;20(5):265-72
Chromosomal aberrations analysis in a brazilian
population exposed to pesticides.
Antonucci GA, de Syllos Colus IM
Department of General Biology, CCB,
State University of Londrina, PR, Brazil.
In spite of being harmful, pesticides are widely
used in Brazil. Their genotoxic effects might be
studied through population monitoring by means
of the analysis of chromosomal aberrations in
occupationally exposed individuals. The aim of
this study was to evaluate the chromosomal
aberration frequencies in temporary cultures of
lymphocytes from periferic blood of 23 workers
professionally exposed to a mixture of pesticides.
The workers were employed by the Agronomic
Institute of Parana (Brazil) and used all of the
prevention measures provided. A detailed history of
pesticide use, as well as personal data, smoking habits,
and history of recent illnesses and medical
treatment were collected through a standardized
questionnaire administered to each subject.
Nonexposed subjects, matched for age, sex, and
smoking habits, served as the negative control.
A total of 100 cells were analyzed from each
individual. A significant increase in chromosomal
aberration frequencies was observed in exposed
individuals when compared to the control group.
Some individual characteristics such as age, sex,
time of exposure to the pesticides, and smoking
habits showed no correlation with chromosomal
aberrations. Therefore, the positive results may
be considered true effects of pesticides on human
somatic cells. PMID: 10992273, UI: 20449336
Carcinogenesis 2000 Aug;21(8):1573-80
Loss of DNA-protein crosslinks from
formaldehyde-exposed cells occurs
through spontaneous hydrolysis and an active repair
process linked to proteosome function.
Quievryn, George A. ; Zhitkovich, Anatoly
Department of Pathology and Laboratory Medicine,
Brown University, Box G-B511, Providence, RI 02912, USA.
George_Quievryn@brown.edu
Anatoly_Zhitkovich@brown.edu
DNA-protein crosslinks (DPC) involving all major
histones are the dominant form of DNA
damage in formaldehyde-exposed cells. In order to
understand the repair mechanisms for these
lesions we conducted detailed analysis of the
stability of formaldehyde-induced DPC in vitro and
in human cells. DNA-histone linkages were found to
be hydrolytically unstable, with t(1/2) = 18.3 h
at 37 degrees C. When histones were allowed to
remain bound to DNA after crosslink
breakage, the half-life of DPC increased to 26.3 h.
This suggests that approximately 30% of
spontaneously broken DPC could be re-established
under physiological conditions. The half-lives
of DPC in three human cell lines (HF/SV fibroblasts,
kidney Ad293 and lung A549 cells) were
similar and averaged 12.5 h (range 11.6-13.0 h).
After adjustment for spontaneous loss, an active
repair process was calculated to eliminate DPC from
these cells with an average t(1/2) = 23.3 h.
Removal of DPC from peripheral human lymphocytes was
slower (t(1/2) = 18.1 h), due to
inefficient active repair (t(1/2) = 66.6 h). This
indicates that the major portion of DPC is lost from
lymphocytes through spontaneous hydrolysis rather
than being actively repaired. Depletion of
intracellular glutathione from A549 cells had no
significant effect on the initial levels of DPC, the
rate of their repair or cell survival. Nucleotide
excision repair does not appear to be involved in the
removal of DPC, since the kinetics of DPC
elimination in XP-A and XP-F fibroblasts were very
similar to normal cells. Incubation of normal or
XP-A cells with lactacystin, a specific inhibitor of
proteosomes, caused inhibition of DPC repair,
suggesting that the active removal of DPC in cells
may involve proteolytic degradation of crosslinked
proteins. XP-F cells showed somewhat higher
sensitivity to formaldehyde, possibly signaling
participation of XPF protein in the removal of
residual peptide-DNA adducts.
PMID: 10910961, UI: 20372597
Toxicol Vitr 2000 Aug;14(4):287-95
In vitro genotoxicity of ethanol and acetaldehyde in
human lymphocytes
and the gastrointestinal tract mucosa cells.
Blasiak J, Trzeciak A, Malecka-Panas E, Drzewoski J,
Wojewodzka M
Department of Molecular Genetics, University of
Lodz, 12/16, 90-237 Lodz, Banacha, Poland.
januszb@biol.uni.lodz.pl
The influence of ethanol and acetaldehyde on DNA in
human lymphocytes, gastric mucosa (GM)
and colonic mucosa (CM) was investigated by using
the comet assay. All kinds of cells were
exposed to ethanol and acetaldehyde in two regimens:
the cells were incubated with either
chemical and analysed or they were exposed first to
ethanol, washed and then exposed to
acetaldehyde and analysed. Lymphocytes were exposed
to ethanol at final concentrations of 30
mM and acetaldehyde at 3 mM. GM cells were incubated
with ethanol at 1 M and acetaldehyde
at 100 mM. CM cells were exposed to ethanol at 10 mM
and acetaldehyde at 100 mM. In
combined exposure, the cells were subsequently
exposed to ethanol and acetaldehyde at all
combination of the concentrations of the agents.
Ethanol caused DNA strand breaks, which were
repaired during 4 hr, except when this agent was
applied in GM cells at a concentration of 1 M. A
dose-dependent decrease in the tail moment of all
types of acetaldehyde-treated cells was
observed. Similar results were obtained when a
recognized DNA crosslinking agent,
formaldehyde, was used. These results suggest that
acetaldehyde may form crosslinks with DNA.
These crosslinks were poorly repaired. CM cells
showed the highest sensitivity of all cell types to
ethanol than lymphocytes and GM cells. There were no
differences in the sensitivity to
acetaldehyde of all the cell types. Our results
clearly indicate that ethanol and acetaldehyde can
contribute to cancers of the digestive tract.
PMID: 10906435, UI: 20368927
Mutat Res 2000 Jul 10;468(2):93-108
Validation of single cell gel assay in human
leukocytes with 18 reference compounds.
Frenzilli G, Bosco E, Barale R
Dipartimento di Scienze dell'Uomo e dell'Ambiente,
Universita di Pisa, Italy. r.barale@geog.unipi.it
To validate the alkaline single cell gel (SCG) assay
as a tool for the detection of DNA damage in
human leukocytes, we investigated the in vitro
activity of 18 chemicals. Thirteen of these chemicals
(pyrene (PY), benzo(a)pyrene (BaP), cyclophosphamide
(CP), 4-nitroquinoline-1-oxide
(4NQO), bleomycin (BLM), methylmercury chloride
(MMC), mitomycin C (MTC), hydrogen
peroxide (HP), diepoxybutane (DEB), glutaraldehyde
(GA), formaldehyde (FA), griseofulvin
(GF), sodium azide (NA)) are genotoxic in at least
one cell system, while five compounds
(ascorbic acid (AA), glucose (GL), D-mannitol (MAN),
O-vanillin (VAN), chlorophyllin (CHL))
are classified as non-genotoxic. In this in vitro
SCG assay, PY, BaP and CP were positive with
exogeneous metabolic activation (rat S9 mix) while
4NQO, BLM, MMC, MTC, hydrogen
peroxide, and diepoxbutane were positive in the
absence of metabolic activation. CHL and VAN
were unexpectedly found to induce a dose-dependent
increase in DNA migration. AA, GL, and
MAN were negative in a non-toxic range of doses. GF
gave equivocal results, while FA and GA
increased DNA migration at low doses and decreased
DNA migration at higher doses. This
behaviour is consistent with the known DNA damaging
and crosslinking properties of these
compounds. These data support the sensitivity and
specificity of this assay for identifying genotoxic agents.
PMID: 10882888, UI: 20342076
Mutat Res 1999 Sep;437(2):151-63
Comparison of the spectra of genetic damage in
formaldehyde-induced ad-3
mutations between DNA repair-proficient and
-deficient heterokaryons of Neurospora crassa.
de Serres FJ, Brockman HE
Mammalian Mutagenesis Group, Laboratory of
Toxicology, Systems Toxicology Branch,
Environmental Toxicology Program, National Institute
of Environmental Health Sciences,
Research Triangle Park, NC 27703-27709, USA.
deserres@niehs.nih.gov 919-541-3345 info
The mutagenic effects of formaldehyde (FA) have been
compared in DNA repair-proficient
(heterokaryon 12) and DNA repair-deficient
(heterokaryon 59) two-component heterokaryons of
Neurospora crassa. The data from forward-mutation
experiments were used to compare the
spectra of FA-induced specific-locus mutations at
two closely linked loci in the adenine-3 (ad-3)
region and on the FA-induced inactivation of
heterokaryotic conidia. Previous studies have
demonstrated that specific-locus mutations at these
two loci result from five major genotypic
classes, namely two classes of gene/point mutations
(ad-3A(R) and ad-3B(R)), and three classes
of multilocus deletion mutations ([ad-3A](IR),
[ad-3B](IR), and [ad-3A ad-3B](IR)). Genetic
analysis of ad-3 mutants recovered from both
heterokaryons after FA treatment demonstrates that
predominantly gene/point mutations were found in
H-12 (93.2% ad-3(R), 6.8% [ad-3](IR)) and a
significantly higher frequency of multilocus
deletion mutations in H-59 (62.8% ad-3(R), 37.0%
[ad-3](IR)). The data from our experiments with FA
on H-12 demonstrate and confirm the data
from other assays that FA is a weak mutagen in this
DNA repair-proficient strain. However, the
data from our experiments with the DNA
repair-deficient strain H-59 demonstrate that
comparable concentrations of FA cause more
pronounced inactivation of heterokaryotic conidia
and, at the highest concentration tested, about a
35-fold higher frequency of ad-3 mutations. In
addition, FA induced a 5.4-fold higher frequency of
ad-3 mutations resulting from multilocus
deletion mutation in H-59 than in H-12. Based on our
earlier studies with X-ray-induced
multilocus deletion mutations, it is this class of
FA-induced ad-3 mutations that might be most
expected to show deleterious heterozygous effects.
The implications of the present data base from
our experiments with Neurospora are that the
mutagenic (and possibly the carcinogenic) effect of
FA exposure might well vary in different human
population subgroups. PMID: 10556619, UI: 20027293
Toxicol Appl Pharmacol 1999 Oct 1;160(1):86-100
Pharmacodynamics of formaldehyde: applications of a
model for the arrest of DNA replication
by DNA-protein cross-links.
Heck H, Casanova M
Chemical Industry Institute of Toxicology, Research
Triangle Park, North Carolina 27709, USA.
casaheck@beaufortco.com
A variety of evidence suggests that formaldehyde
(HCHO)-induced DNA-protein cross-links
(DPX) are genotoxic as a result of their ability to
arrest DNA replication. Although DPX can be
removed and the DNA can be repaired, failure to
remove the blockage prior to cell division or
excision followed by incomplete repair could cause
cell death or a mutation. To characterize the
concentration and time dependence of this mechanism,
a biologically based model for DNA
replication in the presence of DPX was developed
based on the assumptions that (1) DPX are
formed randomly in the DNA and (2) a replication
fork can advance up to but not past a DPX.
Using a combination of Poisson and binomial
statistics, a quantitative relationship between the
amount of newly synthesized DNA and the
concentration of DPX was derived, which predicts
that the rate of DNA replication should decrease
nonlinearly with increasing concentrations of
DPX. Because the latter is a nonlinear function of
the airborne concentration of HCHO, an inverse
sigmoidal relationship is predicted between the rate
of DNA replication and the concentration of
inhaled formaldehyde. The model was parameterized
using data derived from a study of the
incorporation of [methyl-(14)C]thymidine
monophosphate into the DNA of the nasal respiratory
mucosa of Fischer-344 rats exposed to (3)HCHO and
H(14)CHO (6 ppm, 6 h). The model was
then applied to measurements of DNA replication in
the nasal mucosa of experimental animals
exposed to wide ranges of H(14)CHO (rats: 0.7, 2, 6,
or 15 ppm, 3 h; rhesus monkeys: 0.7, 2,
or 6 ppm, 6 h). The results indicate that, at
airborne concentrations above 6 ppm in rats, there is a
marked decrease (ca. 62% at 15 ppm) in the amount of
newly synthesized DNA due to DPX
formation during a single 6-h exposure to HCHO. The
arrest of DNA replication at high HCHO
concentrations could result in cytolethality or
genotoxicity, both of which are critical factors in the
induction of rat nasal cancer by HCHO. However, at
concentrations below 2 ppm in monkeys or
1 ppm in rats, the decrease in the rate of DNA
replication is predicted to be <1% after a 6-h
exposure. This small decrease is probably
undetectable using currently available techniques. The
parameterized model suggests that the arrest of DNA
replication by DPX is mainly a high-dose
phenomenon and that at ambient exposure
concentrations it is unlikely to be a major risk factor.
PMID: 10502505, UI: 99434227
Risk Anal 2000 Apr;20(2):273-91
Air toxics and health risks in California: the
public health implications of outdoor concentrations.
Morello-Frosch RA, Woodruff TJ, Axelrad DA, Caldwell JC
University of California-Berkeley, School of Public
Health, Environmental Health Sciences Division
94720-7360, USA. rmf@uclink.berkeley.edu
woodruff.tracey@epa.gov
Caldwell.Jane@epamail.epa.gov
Of the 188 hazardous air pollutants (HAPs) listed in
the Clean Air Act, only a handful have
information on human health effects, derived
primarily from animal and occupational studies. Lack
of consistent monitoring data on ambient air toxics
makes it difficult to assess the extent of
low-level, chronic, ambient exposures to HAPs that
could affect human health, and limits attempts
to prioritize and evaluate policy initiatives for
emissions reduction. Modeled outdoor HAP
concentration estimates from the U.S. Environmental
Protection Agency's Cumulative Exposure
Project were used to characterize the extent of the
air toxics problem in California for the base
year of 1990. These air toxics concentration
estimates were used with chronic toxicity data to
estimate cancer and noncancer hazards for individual
HAPs and the risks posed by multiple
pollutants. Although hazardous air pollutants are
ubiquitous in the environment, potential cancer
and noncancer health hazards posed by ambient
exposures are geographically concentrated in
three urbanized areas and in a few rural counties.
This analysis estimated a median excess
individual cancer risk of 2.7E-4 for all air toxics
concentrations and 8600 excess lifetime cancer
cases, 70% of which were attributable to four
pollutants: polycyclic organic matter, 1,3 butadiene,
formaldehyde, and benzene. For noncancer effects,
the analysis estimated a total hazard index
representing the combined effect of all HAPs
considered. Each pollutant contributes to the index a
ratio of estimated concentration to reference
concentration. The median value of the index across
census tracts was 17, due primarily to acrolein and
chromium concentration estimates. On
average, HAP concentrations and cancer and noncancer
health risks originate mostly from area
and mobile source emissions, although there are
several locations in the state where point sources
account for a large portion of estimated
concentrations and health risks. Risk estimates from this
study can provide guidance for prioritizing
research, monitoring, and regulatory intervention
activities to reduce potential hazards to the
general population. Improved ambient monitoring
efforts can help clarify uncertainties inherent in
this analysis. PMID: 10859786, UI: 20317367
Ann Allergy Asthma Immunol 1999 Dec;83(6 Pt 2):618-23
Toxicologic considerations in the diagnosis of
occupational asthma.
Waddell, William "Bill" J. bwaddell@louisville.edu
Department of Pharmacology and Toxicology, School of
Medicine, University of Louisville, Kentucky, USA.
BACKGROUND: The consideration of dose for chemicals
inducing occupational asthma is
examined from the point of view of a toxicologist.
Two widely used chemicals in industry, toluene
diisocyanate (TDI) and formaldehyde, are used as
examples of agents that are formally recognized
by OSHA to cause occupational asthma. The
Permissible Exposure Limit (PEL) of OSHA and
the Threshold Limit Value (TLV) of ACGIH for TDI are
identical and are in the range of values
for which occupational asthma has been reported in
some workers. The narrow range of exposure
values for TDI in studies of workers with and
without asthma is discussed and correlated with the
background concentration of TDI in the ambient
atmosphere. For formaldehyde, the PEL and
TLV, in contrast, offer a wide margin of safety for
the inducement of occupational asthma.
CONCLUSION: From this disparity in exposure limits
for TDI and formaldehyde, it is concluded
that occupational exposure limits by agencies for
specific chemicals do not provide a reliable
indication of the concentration of a chemical that
is necessary to produce occupational asthma.
The need for a better appreciation of dose response,
particularly relative to background, ambient
levels, in the evaluation of occupational asthma is
emphasized. PMID: 10619332, UI: 20084350
Toxicol Environ Health 1999 Jul 23;57(6):431-42
Activity of cathepsin G, elastase, and their
inhibitors in plasma during methanol intoxication.
Skrzydlewska E, Szmitkowski M, Farbiszewski R
Department of Analytical Chemistry, Medical
University, Bialystok, Poland. skrzydle@amb.ac.bialystok.pl
Methanol oxidation in the liver is accompanied by
formation of formaldehyde and free radicals.
These compounds can react with biologically active
proteins, including proteolytic enzymes and
their inhibitors. The activity of cathepsin G and
elastase and their inhibitors such as
alpha-1-antitrypsin and alpha-2-macroglobulin in
plasma of rats given methanol orally in doses of
1.5, 3, and 6 g/kg was investigated for 7 days. The
activity of cathepsin G and elastase was
increased from 12 h to 5 d, proportionally to
methanol dose. At the same time, activity of their
inhibitors was reduced. Methanol ingestion in humans
caused changes in activities of proteases and
their inhibitors with similar direction as in rats.
These changes in activity of proteases and their
inhibitors produce significant disturbances in
proteolytic-antiproteolytic balance after methanol
administration. PMID: 10478824, UI: 99405938
Pathol Res Pract 2000;196(3):193-8
Formaldehyde neurotoxicity in animal experiments.
Pitten FA, Kramer A, Herrmann K, Bremer J, Koch S
Institute of Hygiene and Environmental Medicine,
[Institut fur Hygiene und Umweltmedizin]
Ernst-Moritz-Arndt-University, Greifswald, Germany.
pitten@rz.uni-greifswald.de
The aim of this study was to determine whether the
inhalation of formaldehyde has a
neurotoxicological impact. Forty Wistar rats
(Lew.1/K) were trained to find food in a maze within
a particular time. When all animals were at an equal
level, 13 rats inhaled 2.6 ppm and 13 others
inhaled 4.6 ppm formaldehyde 10 min/d, 7 d/week for
90 d. The control group comprised 14
animals inhaling water steam according to the same
exposure pattern. During the exposure period
and the post-trial observation stage (30 d), the
time required to find the food and the number of
mistakes made on the way were recorded. Between the
animals exposed to formaldehyde and the
control group a statistically significant difference
for both parameters was observed (p < 0.05).
The animals exposed to formaldehyde needed more time
and made more mistakes than the
animals of the control group while going through the
maze. The results underline the necessity for a
systematic observance of precautions in case of
occupational or dwelling-related formaldehyde
exposure, and allow us to classify formaldehyde as
"probably neurotoxic". Further investigations
are required to assess the neurotoxicologic impact
of subchronic formaldehyde exposure.
PMID: 10729924, UI: 20194117
Human &
Experimental Toxicology (2000) 19, 360-366.
Toxicity of ingested formalin and its management.
Pandey CK, Agarwal A, Baronia A, Singh N
Department of Anaesthesiology and Critical Care
Medicine, Sanjay Gandhi Postgraduate Institute
of Medical Sciences, Lucknow 226014, India.
ckpandey@sgpgi.ac.in
Formaldehyde is a physiological intermediary
metabolite taking part in many biological process in
the body. It is a constituent of many items of daily
use, including foods. It is also used in medicine
for treatment of some conditions. A 40% solution of
formaldehyde in water is known as formalin.
Formalin is irritating, corrosive and toxic and
absorbed from all surfaces of the body. Ingestion is
rare because of alarming odour and irritant effect
but documented in accidental, homicidal or
suicidal attempts. Ingestion can lead to immediate
deleterious effects on almost all systems of the
body including gastrointestinal tract, central
nervous system, cardiovascular system and
hepato-renal system, causing gastrointestinal
hemorrhage, cardiovascular collapse,
unconsciousness or convulsions, severe metabolic
acidosis and acute respiratory distress
syndrome. No specific antidote is available.
Treatment of toxicity is supportive care of the various
organ systems. Multidisciplinary approach is
required for proper management.
PMID: 10962510
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Rich Murray, MA Room For All rmforall@att.net
1943 Otowi Road, Santa Fe NM USA 87505 505-986-9103
http://groups.yahoo.com/group/aspartameNM/messages for 863 posts
http://groups.yahoo.com/group/aspartameNM/message/861 brief summary
http://groups.yahoo.com/group/aspartameNM/message/862 long summary
http://groups.yahoo.com/group/aspartameNM/message/860
RTM: FDA: objections to neotame approval (Section A) 8.4.2 rmforall
Rich Murray: Serious symptom syndrome summary:
Aspartame (NutraSweet, Equal, Canderel, Benevia) is reported by
scientific studies and case histories to be toxic: * headaches
* many body and joint pains (or burning, tingling, tremors, twitching,
spasms, cramps, or numbness) * fever, fatigue
* "mind fog", "feel unreal", poor memory, confusion, anxiety,
irritability, depression, mania, insomnia, dizziness, slurred speech,
ringing in ears, sexual problems, poor vision, hearing, or taste
* red face, itching, rashes, burning eyes or throat,
dry mouth or eyes, mouth sores * hair loss
* obesity, bloating, edema, anorexia,
poor or excessive hunger or thirst * breathing problems
* nausea, diarrhea or constipation * coldness * sweating
* racing heart, high blood pressure, erratic blood sugar levels
* seizures * birth defects * brain cancers * addiction
* aggrivates diabetes, autism, ADHD,
and interstitial cystitis (bladder pain).
Almost all are typical of chronic methanol-formaldehyde toxicity:
for detailed review http://www.dorway.com/barua.html
Journal Of The Diabetic Association Of India
1995 Vol. 35, No. 4. Emerging Facts About Aspartame
Dr. J. Barua (ophthalmic surgeon), Dr. Arun Bal (surgeon)
(79 references) barua@giasbm01.vsnl.net.in
"...the total amount of methanol absorbed will be approximately
10% of aspartame ingested. An EPA assessment of methanol states
that methanol "is considered a cumulative poison due to the low rate
of excretion once it is absorbed." The absorbed methanol is then
slowly converted to formaldehyde..."
"Reaction of formaldehyde with DNA has been observed,
by spectrophotometry and electron microscopy, to result in
irreversible denaturation."
http://groups.yahoo.com/group/aspartameNM/message/830
RTM: Tholen: Diet Coke has 5 ppm formaldehyde from aspartame
5.29.2 rmforall
For 6 cans of diet soda, this is 5 times the daily limit of 1 PPM for
formaldehyde in drinking water, set by the EPA.
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